1342, oral, Cat: 2
REGULATION OF MACROPHAGE SCAVENGER RECEPTOR EXPRESSION -
NEW PLEIOTROPIC EFFECTS OF STATINS
J Han , X Zhou, M Parson, AC Nicholson, AM Gotto, Jr., T Yokoyama, DP Hajjar
Weill Medical College of Cornell University, New York, NY, USA
Formation of lipid-loaded macrophage foam cells is the initial and critical step in development of atherosclerosis. Macrophage scavenger receptor type B (CD36) binds and internalizes oxidized low density lipoprotein (OxLDL). Macrophage scavenger receptor type BI (SR-BI) uptakes high density lipoprotein (HDL) and mediates cholesterol efflux. CD36 and SR-BI play opposite roles in formation of atherosclerotic lesions respectively. Statins are novel inhibitors of 3-hydroxy-3-methylglutaryl coenzyme
A (HMG-CoA) reductase, the rate-limiting enzyme for cholesterol synthesis. In addition to the decreased serum LDL cholesterol and triglyceride levels and increased HDL cholesterol level, statins also demonstrate cholesterol-lowering independent effects to vascular system. Herein we studied the effects of pitavastatin (NK-104), a newly synthesized statin, on macrophage CD36 and SR-BI expression. Treatment of murine macrophages with pitavastatin decreased CD36 mRNA expression while increased SR-BI mRNA expression. Changes in transcripts were associated with changes in CD36 and
SR-BI protein as well as function respectively. Mechanism studies indicated that pitavastatin decreased macrophage CD36 expression by decreasing peroxisome proliferator-activated receptor-gamma (PPAR-gamma) expression and increasing the ration of phosphorylated PPAR-gamma to nonphosphorylated PPAR-gamma. The upregulation of macrophage SR-BI expression was completed by pitavastatin-mediated reduction of cholesterol biosynthetic intermediates and anti-inflammatory action. Our studies suggest additional pleiotropic effects of statins by which they may reduce the incidence of coronary heart disease.